P1048: PHARMACOKINETIC AND PHARMACODYNAMIC EFFECTS OF RUSFERTIDE IN POLYCYTHEMIA VERA: RESULTS FROM AN ONGOING PHASE 2 STUDY IN PATIENTS WITH ELEVATED HEMATOCRIT VALUES
Authors: Marina Kremyanskaya, Lee Ping Chew, Sneha Rudraraju, Suneel Gupta, Nishit Modi
Journal: HemaSphere (2023)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis defined by an acquired increase in hemoglobin (Hb)/hematocrit (HCT). The therapeutic goal for treating patients with PV is maintaining HCT below 45%, thereby reducing thrombotic events. Rusfertide is a potent hepcidin mimetic that targets the ferroportin receptor, which functions as a transmembrane channel for the transport of cellular iron. Through its effects of restricting iron availability for erythropoiesis, rusfertide may be effective for PV. Studies in patients with PV indicate rusfertide results in rapid, sustained and durable HCT control, independent of patient risk category or concurrent therapy with hydroxyurea, interferon or ruxolitinib. Aims: To understand the relationship between rusfertide plasma concentrations and efficacy in patients with PV. Methods: PTG-300-08 (NCT04767802, PACIFIC study) is an open-label, phase 2 study in progress investigating the efficacy of rusfertide in patients with poor HCT control as noted by HCT >48%. Subjects with high- or low-risk PV are eligible and concurrent cytoreductive therapy is allowed. Treatment is initiated with 40 mg rusfertide subcutaneously (SC) twice a week. After the HCT is controlled to <45%, the treatment is changed to 40 mg once a week and subsequently the dose can be adjusted to maintain HCT <45%. Twenty Asian patients (15 males, 5 females) with average age 65.0±10.9 years were enrolled. Patients provided informed consent prior to any study-related procedures. Plasma samples were collected over the course of the study for measurement of rusfertide concentrations (PK), hemoglobin (Hb), and other clinical laboratory parameters. This analysis develops an integrated PK/efficacy (PD) model relating rusfertide PK to Hb and examines patient covariates using a posthoc analysis. PK was described by first-order absorption from the SC injection site. The efficacy is related to PK through an effect compartment using an indirect response relationship. The PD model envisions a constant production (input) of Hb/HCT which is inhibited by rusfertide. Results: The integrated PK-efficacy model adequately described the rusfertide plasma concentration-time profile and the time course of Hb. The population mean absorption rate, apparent volume of distribution, and apparent clearance were 0.188 h-1, 49.0 L, and 0.98 L/h, respectively. Estimated mean baseline Hb was 15.9 g/dL and the maximum inhibitory effect was 24.7% corresponding to 3.9 g/dL decrease in the estimated mean baseline Hb. Post-hoc analyses of the apparent clearance relative to patient characteristics (risk category, gender, weight, age) suggested that apart from body weight (<65 kg versus >65 kg), there were minimal effects of other patient characteristics examined (Fig 1A). The relationship between rusfertide PK and the Hb response in representative patients is shown in Fig 1B. The model adequately recapitulated the time course of the onset of effect upon initiating rusfertide, loss in response during dosing suspension, and subsequent rapid return in response upon reinitiating therapy. Overall, the model adequately described the effect of changes in therapeutic regimen in a subject Summary/Conclusion: The hemoglobin response tracks rusfertide plasma concentrations. The integrated concentration-hemoglobin relationship showed rapid onset and subsequent maintenance in hemoglobin-time course following initiation of rusfertide and the loss in effect upon dosing suspension.Keywords: Hemoglobin, Pharmacokinetic, Polycythemia vera, Rusfertide